Malaria is caused by eukaryotic parasites that display distinct surface antigens during three independent stages of the life cycle: initial infection caused by the pre-erythrocytic stage, clinical symptoms as a result of the blood stage, and transmission by the mosquito stage. While both T-cell and B-cell responses play a role in naturally acquired immunity to malaria, focusing the B-cell responses on conserved broadly-neutralizing functional epitopes significantly improves protection and may lead to sterile immunity. Three aspects of parasite biology confound malaria vaccine development: (1) antigenic variability across strains and species, (2) the presence of immunodominant but non-neutralizing epitopes in antigens, and (3) the diverse, numerous, and often redundant parasite antigens required for each stage of the life cycle. The explosion in technology for structural vaccinology and the structural definition of neutralizing epitopes in key malaria antigens motivates the structure-guided design of immunogens for malaria vaccine development targeting all stages of the life cycle. We propose to leverage the existing structural information of malaria antigen and neutralizing antibody complexes to design improved immunogens and nanoparticles that will elicit protective immune responses. Immunogens will be improved through protein design to retain neutralizing epitopes, eliminate non-neutralizing epitopes and present optimized immunogens on nanoparticles for efficient delivery and immunogenicity. Proteins will be designed using computational approaches to stabilize protein conformations, reduce large proteins to immunogenic subdomains, and scaffold epitopes for efficient presentation. Diverse established nanoparticle platforms will be evaluated for their ability to effectively present antigens, and novel nanoparticles will be developed for delivery. All designed immunogens and nanoparticles will be structurally characterized through x-ray crystallography and cryo electron microscopy to ensure the correct conformational three-dimensional structure of the antigen is retained. We began establishing the framework necessary for these studies in 2019. This included the recruitment of two scientists in February, and developing the computational infrastructure required for the design procedures in conjunction with the NIAID Locus high performance computer cluster. We have developed an in vitro screening platform to validate computationally designed antigens and we have used this platform to identify lead candidates that lack non-neutralizing immunodominant epitopes.